The hormonal change at menopause is arguably the most important biochemical event in a woman's life related to normal as well as pathological cognitive aging. At menopause some women experience declines in memory, attention, problem solving, and motor skills from premenopausal levels. However, not all women experience negative effects of menopause on cognition. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for determining risk factor for pathological aging. We propose that the change in the hormonal milieu at menopause interacts with dopaminergic functioning in the frontal cortex of the brain to influence a woman's risk for cognitive decline after menopause. The Study proposed in this R21 Exploratory/Developmental Research Grant will examine how different genotypes that code for the enzyme catechol-O-methyltransferase (COMT) affect cognition in women after menopause. COMT is an enzyme responsible for dopamine metabolism in the frontal cortex and a common single nucleotide polymorphism (Val158Met) results in different levels of dopamine metabolism that affect cognition. Met/Met compared to Val/Val homozygotes have decreased dopamine metabolism, increased cognitive performance, and decreased frontal cortex activation as measured by functional magnetic resonance imaging (fMRI). Collectively this data pattern is interpreted as more efficient cognitive processing. Estrogen has the ability to directly modulate dopaminergic functioning by interacting with two estrogen response elements on the COMT promotor to decrease COMT transcription and thereby increase dopaminergic functioning and affect dopaminergically driven cognition. Thus, the estradiol change at menopause is likely to have effects on cognitive processes that are regulated by normal dopaminergic functioning and modulated by COMT genotype. This study will recruit healthy postmenopausal women who will perform a working memory task during fMRI, provide a blood sample for genetic and hormone analyses, and perform neuropsychological tests to assess individual differences in cognition after menopause. This study will advance understanding of the genetic mechanisms potentially involved in successful and pathological cognitive aging. This innovative study will impact what is known about the effects of menopause on cognition by 1) allowing for a refinement of theories of cognitive aging by incorporating genetic mechanisms, 2) providing a genetic-based neurotransmitter target for drug discovery to modulate cognition after menopause in addition to the hormone-based strategies, and 3) enabling the prediction of individual vulnerability for pathological aging.